Open AccessSinglet Oxygen Formation vs Photodissociation for Light-Responsive Protic Ruthenium Anticancer Compounds: The Oxygenated Substituent Determines Which Pathway Dominates
Author(s) -
Fengrui Qu,
Robert W. Lamb,
Colin G. Cameron,
Seungjo Park,
Olaitan E. Oladipupo,
Jessica L. Gray,
Yifei Xu,
Houston D. Cole,
Marco Bonizzoni,
Yonghyun Kim,
Sherri A. McFarland,
Cynthia Webster,
Elizabeth T. Papish
Publication year - 2021
Publication title -
inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.348
H-Index - 233
eISSN - 1520-510X
pISSN - 0020-1669
DOI - 10.1021/acs.inorgchem.0c02027
Subject(s) - chemistry , singlet oxygen , photodissociation , ruthenium , photochemistry , quantum yield , diimine , singlet state , photodegradation , deprotonation , substituent , oxygen , medicinal chemistry , stereochemistry , photocatalysis , fluorescence , excited state , catalysis , organic chemistry , ion , physics , quantum mechanics , nuclear physics
Ruthenium complexes bearing protic diimine ligands are cytotoxic to certain cancer cells upon irradiation with blue light. Previously reported complexes of the type [( N , N ) 2 Ru(6,6'-dhbp)]Cl 2 with 6,6'-dhbp = 6,6'-dihydroxybipyridine and N , N = 2,2'-bipyridine (bipy) ( 1 A ), 1,10-phenanthroline (phen) ( 2 A ), and 2,3-dihydro-[1,4]dioxino[2,3- f ][1,10]phenanthroline (dop) ( 3 A ) show EC 50 values as low as 4 μM (for 3 A ) vs breast cancer cells upon blue light irradiation ( Inorg. Chem. 2017, 56, 7519). Herein, subscript A denotes the acidic form of the complex bearing OH groups, and B denotes the basic form bearing O - groups. This photocytotoxicity was originally attributed to photodissociation, but recent results suggest that singlet oxygen formation is a more plausible cause of photocytotoxicity. In particular, bulky methoxy substituents enhance photodissociation but these complexes are nontoxic ( Dalton Trans 2018, 47, 15685). Cellular studies are presented herein that show the formation of reactive oxygen species (ROS) and apoptosis indicators upon treatment of cells with complex 3 A and blue light. Singlet oxygen sensor green (SOSG) shows the formation of 1 O 2 in cell culture for cells treated with 3 A and blue light. At physiological pH, complexes 1 A - 3 A are deprotonated to form 1 B - 3 B in situ . Quantum yields for 1 O 2 (ϕ Δ ) are 0.87 and 0.48 for 2 B and 3 B , respectively, and these are an order of magnitude higher than the quantum yields for 2 A and 3 A . The values for ϕ Δ show an increase with 6,6'-dhbp derived substituents as follows: OMe < OH < O - . TD-DFT studies show that the presence of a low lying triplet metal-centered ( 3 MC) state favors photodissociation and disfavors 1 O 2 formation for 2 A and 3 A (OH groups). However, upon deprotonation (O - groups), the 3 MLCT state is accessible and can readily lead to 1 O 2 formation, but the dissociative 3 MC state is energetically inaccessible. The changes to the energy of the 3 MLCT state upon deprotonation have been confirmed by steady state luminescence experiments on 1 A - 3 A and their basic analogs, 1 B - 3 B . This energy landscape favors 1 O 2 formation for 2 B and 3 B and leads to enhanced toxicity for these complexes under physiological conditions. The ability to convert readily from OH to O - groups allowed us to investigate an electronic change that is not accompanied by steric changes in this fundamental study.